Isoxazoline compounds as antiinflammatory agents

ABSTRACT

PCT No. PCT/IB94/00333 Sec. 371 Date May 15, 1996 Sec. 102(e) Date May 15, 1996 PCT Filed Oct. 26, 1994 PCT Pub. No. WO95/14681 PCT Pub. Date Jun. 1, 1995This invention relates to isoxazoline compounds which are selective inhibitors of phosphodiesterase type IV (PDEIV). The isoxazoline compounds are useful in inhibiting PDEIV and in the treatment of AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, allergic rhinitis, dermatitis, shock, atopic dermatitis, rheumatoid arthritis and osteoarthritis. This invention also relates to pharmaceutical compositions useful therefor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the national stage of International Application No.PCT/IB94/00333, filed Oct. 26, 1994, published as WO/95/14681 on Jun. 1,1995, designating, inter alia, the United States which is acontinuation-in-part of U.S. application Ser. No. 08/262,086, filed Jun.17, 1994, now abandoned which is a continuation-in-part of U.S.application Ser. No. 08/157,248 filed Nov. 26, 1993, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a series of 3-aryl-2-isoxazoline-5-hydroxamicacid compounds which are selective inhibitors of phosphodiesterase typeIV (PDE_(IV)) and as such are useful in the treatment of AIDS, asthma,arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis,allergic rhinitis, dermatitis and other inflammatory conditions.

This invention also relates to the pharmaceutically acceptable salts ofsaid compounds; to a method of using such compounds in inhibitingPDE_(IV), and in the treatment of inflammatory conditions, AIDS, asthma,arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis,allergic rhinitis and dermatitis in mammals, especially humans; and topharmaceutical compositions useful therefor.

The "inflammatory conditions" which can be treated according to thisinvention include, but are not limited to, chronic obstructive pulmonarydisease, shock, atopic dermatitis, bronchitis, rheumatoid arthritis andosteoarthritis.

Since the recognition that cyclic AMP is an intracellular secondmessenger (E. W. Sutherland, and T. W. Rall, Pharmacol. Rev., 1960, 12,265), inhibition of the phosphodiesterases has been a target formodulation and, accordingly, therapeutic intervention in a range ofdisease processes. More recently, distinct classes of PDE have beenrecognized (J. A. Beavo and D. H. Reifsnyder, TIPS, 1990, 11,150), andtheir selective inhibition has led to improved drug therapy (C. D.Nicholson, R. A. Challiss and M. Shahid, TIPS, 1991, 1:2, 19). Moreparticularly, it has been recognized that inhibition of PDE_(IV) canlead to inhibition of inflammatory mediator release (M. W. Verghese etal., J. Mol. Cell Cardiol., 1989, 12 (Suppl. II), S 61) and airwaysmooth muscle relaxation (T. J. Torphy in Directions for New Anti-AsthmaDrugs, eds S. R. O'Donnell and C. G. A, Persson, 1988, 37,Birkhauser-Verlag), Thus, compounds that inhibit PDE_(IV), but whichhave poor activity against other PDE types, would inhibit the release ofinflammatory mediators and relax airway smooth muscle without causingcardiovascular effects or antiplatelet effects.

Certain pyrimidone compounds have been disclosed to be useful asantidepressants by Saccomano et al., in European Patent Application EPO247 725 A2 published Dec. 2, 1987. The same pyrimidone compounds havebeen disclosed to be useful against asthma and certain skin disorders inInternational Patent Application No. PCT/US90/02162, published May 30,1991 as International Publication Number WO 91/07178.

SUMMARY OF THE INVENTION

This invention is concerned with a series of3-aryl-2-isoxazoline-5-hydroxamic acid compounds and to thepharmaceutically acceptable salts of such compounds. These new compoundspossess inhibitory activity against PDE_(IV) and as such are useful intreating inflammatory conditions, AIDS, asthma, arthritis, bronchitis,chronic obstructive pulmonary disease, psoriasis, allergic rhinitis ordermatitis in a mammal, especially humans.

The compounds of the present invention are of the formula (I) ##STR1##the racemic, racemic-diastereomeric mixtures and optical isomers of saidcompounds and the pharmaceutically acceptable salts thereof wherein

m is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

Y¹ and Y² are independently selected from the group consisting ofhydrogen, (C₁ -C₆)alkyl, optionally substituted phenylalkyl having 1 to6 carbons in the alkyl portion, optionally substituted phenoxyalkylhaving 1 to 6 carbons in the alkyl portion, (C₃ -C₇)cycloalkyl,difluoromethyl, trifluoromethyl, fluoro, chloro, bromo, iodo, --OR¹ and--OR² ;

wherein the aromatic portion of the optionally substituted phenylalkyl,and the aromatic portion of the optionally substituted phenoxyalkyl areoptionally independently substituted with (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy,halogen or CF₃ ; R¹ is (C₁ -C₄)alkyl, phenylalkyl having one to fourcarbon atoms in the alkyl portion fluoromethyl, difluoromethyl,trifluoromethyl, or --(CH₂)_(q) -quinoline wherein q is 1,2 or 3;

R² is (C₁ -C₃ alkyl, (C₃ -C₇)cycloalkyl, alkoxyalkyl having 3 to 7carbons in the alkoxy portion and 2 to 4 carbons in the alkyl portion,optionally substituted phenoxyalkyl having 2 to 6 carbons in the alkylportion, optionally substituted phenylalkyl having 1 to 6 carbons in thealkyl portion, bicycloalkyl having 6 to 9 carbons or optionallysubstituted indanyl;

wherein the aromatic portion of the optionally substituted phenylalkyl,the aromatic portion of the optionally substituted phenoxyalkyl and theoptionally substituted indanyl are optionally substituted with (C₁-₄)alkyl, (C₁ -₄)alkoxy, halogen or CF₃ ;

R³ is hydrogen, (C₁ -C₃)alkyl, fluoro(C₁ -C₃)alkyl having 1 to 3 fluoroatoms, mono-hydroxyalkyl having 1 to 3 carbons or alkoxyalkyl having 1to 3 carbons in the alkyl portion and 1 to 3 carbons in the alkoxyportion;

R⁴ is hydrogen, (C₁ -C₅)alkyl, fluoro(C₁ -C₅)alkyl having 1 to 3 fluoroatoms, mono-hydroxyalkyl having 1 to 3 carbons, phenyl, alkoxyalkylhaving 1 to 3 carbons in the alkyl portion and 1 to 3 carbons in thealkoxy portion, aminoalkyl having 1 to 3 carbons, ##STR2## wherein X¹ is(C₁ -C₃) alkyl and n is an integer from 1 to 3, N-alkylaminoalkyl having1 to 3 carbons in the alkylamino portion and 1 to 3 carbons in the alkylportion, (C₃ -C₇)cycloalkyl or N,N-dialkylaminoalkyl having a total of 2to 6 carbons in the dialkylamino portion and 1 to 3 carbons in the alkylportion; R⁵ is hydrogen or (C₁ -C₃)alkyl;

or R³ and R⁴ are taken together with the carbon atoms to which they areattached and form a carbocyclic ring having 4 to 7 carbon atoms.

A preferred group of compounds or the pharmaceutically acceptable saltsthereof are those compounds of the formula (I) wherein Y¹ is --OR¹ andis attached to the 4-position of the phenyl ring; Y² is --OR² and isattached to the 3-position of the phenyl ring and m, n, R¹, R², R³, R⁴and R⁵ are as defined above for formula (I).

A more preferred group of compounds or the pharmaceutically acceptablesalts thereof are those compounds of the formula (I) wherein Y¹ is --OR¹and is attached to the 4-position of the phenyl ring and Y² is --OR² andis attached to the 3-position of the phenyl ring wherein R¹ is (C₁-C₄)alkyl, phenylalkyl having one to four carbon atoms in the alkylportion or --(CH₂)_(q) -quinoline; m is 0; n is 0; and R², R³, R⁴ and R⁵are as defined above for formula (I).

Another more preferred group of compounds or the pharmaceuticallyacceptable salts thereof are those compounds of the formula (I) whereinY¹ is --OR¹ and is attached to the 4-position of the phenyl ring and Y²is --OR² and is attached to the 3-position of the phenyl ring wherein R¹Is (C₁ -C₄)alkyl, phenylalkyl having one to four carbon atoms in thealkyl portion or -(CH₂)_(q) -quinoline; R² is phenylalkyl having 1 to 6carbons in the alkyl portion, (C₃ -C₇)cycloalkyl, or (C₁ l )alkyl; m is0; n is 0; and R³, R⁴ and R⁵ are as defined above for formula (I).

An even more preferred group of compounds or the pharmaceuticallyacceptable salts thereof are those compounds of the formula (I) whereinY¹ is --OR¹ and is attached to the 4-position of the phenyl ring and Y²is --OR² and is attached to the 3-position of the phenyl ring wherein R¹is (C₁ -C₄)alkyl, phenylalkyl having one to four carbon atoms in thealkyl portion or --(CH₂)_(q) -quinoline; R² is 5-phenylpentyl, benzyl,cyclopentyl or methyl; m is 0; n is 0; and R³, R⁴ and R⁵ are as definedabove for formula (I).

A particularly preferred group of compounds or the pharmaceuticallyacceptable salts thereof are those compounds of the formula (I) whereinY¹ is --OR¹ and is attached to the 4-position of the phenyl ring and Y²is --OR² and is attached to the 3-position of the phenyl ring wherein R¹is (C₁ -C₄)alkyl, phenylalkyl having one to four carbon atoms in thealkyl portion or --(CH₂)_(q) -quinoline; R² is 5-phenylpentyl, benzyl,cyclopentyl or methyl; m is 0; n is 0; R³ is hydrogen and R⁴ and R⁵ areas defined above for formula

Another particularly preferred group of compounds or thepharmaceutically acceptable salts thereof are those compounds of theformula (I) wherein Y¹ is --OR¹ and is attached to the 4-position of thephenyl ring and Y² is --OR² and is attached to the 3-position of thephenyl ring wherein R¹ is (C₁ -C₄)alkyl, phenylalkyl having one to fourcarbon atoms in the alkyl portion or --(CH₂)_(q) -quinoline; R² is5-phenylpentyl, benzyl, cyclopentyl or methyl; m is 0; n is 0; R³ ishydrogen; R⁴ is hydrogen or (C₁ -C₅) alkyl and R⁵ is as defined abovefor formula (I).

A more particularly preferred group of compounds or the pharmaceuticallyacceptable salts thereof are those compounds of the formula (I) whereinY¹ is --OR¹ and is attached to the 4-position of the phenyl ring and Y²is --OR² and is attached to the 3-position of the phenyl ring wherein R¹is (C₁ -C₄)alkyl, phenylalkyl having one to four carbon atoms in thealkyl portion or --(CH₂)_(q) -quinoline; R² is 5-phenylpentyl, benzyl,cyclopentyl or methyl; m is 0; n is 0; R³ is hydrogen; R⁴ is hydrogen or(C₁ -C₅)alkyl and R⁵ is hydrogen or (C₁ -C₃)alkyl; a compound or thepharmaceutically acceptable salt thereof of the formula (I) wherein Y¹is --OR¹ and is attached to the 4-position of the phenyl ring and Y² is--OR² and is attached to the 3-position of the phenyl ring wherein R¹ ismethyl; R² is cyclopentyl; m is 0; n is 0; R³ is hydrogen; R⁴ ishydrogen; and R⁵ is hydrogen; and the levorotatory (negative rotation)isomer of a compound or the pharmaceutically acceptable salt thereof ofthe formula (I) wherein Y¹ is --OR¹ and is attached to the 4-position ofthe phenyl ring and Y² is --OR² and is attached to the 3-position of thephenyl ring wherein R¹ is methyl; R² is cyclopentyl; m is 0; n is 0; R³is hydrogen; R⁴ is hydrogen; and R⁵ is hydrogen.

Another more particularly preferred group of compounds or thepharmaceutically acceptable salts thereof are those compounds of theformula (I) wherein Y¹ is --OR¹ and is attached to the 4-position of thephenyl ring and Y² is --OR² and is attached to the 3-position of thephenyl ring wherein R¹ is methyl; R² is cyclopentyl; m is 0; n is 0; R³is hydrogen; R⁴ is methyl; and R⁵ is hydrogen; and the levorotatory(negative rotation) isomer of a compound or the pharmaceuticallyacceptable salt thereof of the formula (I) wherein Y¹ is --OR¹ and isattached to the 4-position of the phenyl ring and Y² is --OR² and isattached to the 3-position of the phenyl ring wherein R¹ is methyl; R²is cyclopentyl; m is 0; n is 0; R³ is hydrogen; R⁴ is methyl; and R⁵ ishydrogen.

The term alkyl encompasses both straight and branched chains. Thearomatic portion of the optionally substituted phenylalkyl, the aromaticportion of the optionally substituted phenoxyalkyl and the optionallysubstituted indanyl may be substituted by one or more substituents.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention having the formula (I) arecomprised of the racemic, racemic-diastereomeric mixtures and opticalisomers of said compounds and the pharmaceutically acceptable saltsthereof. The compounds of the present invention, having the formula I asdefined above, are readily and generally prepared by the followingreaction process.

To an alcoholic solution of sodium methoxide is added an alcoholicsolution of hydroxylamine hydrochloride and a compound of the formula##STR3## wherein Y¹, Y², R³, R⁴, m and n are as defined above for thecompound of formula (I), and X is an alkyl group. The reaction mixtureis stirred for about 12 to 24 hours, preferably 16 hours, at roomtemperature. The solvent is evaporated and the residue is worked-upaccording to methods well known to those skilled in the art.

The intermediate ester compounds of the formula ##STR4## wherein Y¹, Y²,R³, R⁴, m and n are as defined above for the compound of formula (I),and X is an alkyl group, are synthesized according to the followingprocedure. To a mixture of N-chlorosuccinimide and pyridine in an inertsolvent, such as methylene chloride, is added an oxide of the formula##STR5## wherein Y¹ and Y² are as defined above for formula (I). Themixture is allowed to stir for about 2 to 5 hours, preferably about 2hours. A compound of the formula ##STR6## wherein R³ and R⁴ are asdefined above for formula I and X is an alkyl group, is added followedby the addition of triethylamine to the mixture and the mixture stirredfor about 2 hours more at room temperature. The reaction is worked upaccording to methods well known to those skilled in the art.

The synthetic method outlined above together with the following examplesdescribe methods which were and can be employed to prepare the compoundsof this invention.

Where possible, as ascertained by one skilled in the art enabled by thisdisclosure, pharmaceutically-acceptable acid addition salts of certaincompounds of this invention include, but are not limited to, thoseformed with HCl, HBr, HNO₃, H₂ SO₄, H₃ PO₄, CH₃ SO₃ H, p-CH₃ C₆ H₄ SO₃H, CH₃ CO₂ H, gluconic acid, tartaric acid, maleic acid and succinicacid. In the case of those compounds of the formula (I) which contain afurther basic nitrogen, it will, of course, be possible to form diacidaddition salts (e.g., the dihydrochloride) as well as the usual monoacidaddition salt. Where possible, as ascertained by one skilled in the artenabled by this disclosure, pharmaceutically-acceptable cationic saltsof certain compounds of this invention include, but are not limited to,those of sodium, potassium, calcium, magnesium, ammonium,N,N'-dibenzylethylenediamine, N-methylglucamine (meglumine),ethanolamine and diethanolamine.

The starting materials and reagents required for the synthesis of thecompounds of the present invention are readily available, eithercommercially, according to literature methods, or by methods exemplifiedin Preparations below.

The ability of the compounds or the pharmaceutically acceptable saltsthereof to inhibit PDE_(IV) and, consequently, demonstrate theireffectiveness for treating inflammatory conditions is shown by thefollowing in vitro assays.

BIOLOGICAL ASSAYS Human Lung PDE_(IV)

Thirty to forty grams of human lung tissue is placed in 50 mL of pH 7.4Tris/phenylmethylsulfonyl fluoride (PMSF)/sucrose buffer and homogenizedusing a Tekmar Tissumizer® (Tekmar Co., 7143 Kemper Road, Cincinnati, OH45249) at full speed for 30 seconds. The homogenate is centrifuged at48,000×g for 70 minutes at 4° C. The supernatant is filtered twicethrough a 0.22 μm filter and applied to a Mono-Q FPLC column (PharmaciaLKB Biotechnology, 800 Centennial Avenue, Piscataway, NJ 08854)pre-equilibrated with pH 7.4 Tris/PMSF buffer. A flow rate of 1mL/minute is used to apply the sample to the column, followed by a 2mL/minute flow rate for subsequent washing and elution. Sample is elutedusing an increasing, step-wise NaCl gradient in the pH 7.4 Tris/PMSFbuffer. Eight mL fractions are collected. Fractions are assayed forspecific PDE_(IV) activity, determined by ³ H!cAMP hydrolysis and theability of a known PDE_(IV) inhibitor (e.g. rolipram) to inhibit thathydrolysis. Appropriate fractions are pooled, diluted with ethyleneglycol (2 mL ethylene glycol/5 mL of enzyme prep) and stored at -20° C.until use.

Compounds are dissolved in DMSO at a concentration of 10 mM and diluted1:25 in water (400 μM compound, 4% DMSO). Further serial dilutions aremade in 4% DMSO to achieve desired concentrations. Final DMSOconcentration in the assay tube is 1%. In duplicate the following areadded, in order, to a 12×75 mm glass tube (all concentrations are givenas final concentrations in assay tube).

i) 25 μl compound or DMSO (1%, for control and blank)

ii) 25 μl pH 7.5 Tris buffer

iii) ³ H!cAMP (1 μM)

iv) 25 μl PDE_(IV) enzyme (for blank, enzyme is preincubated in boilingwater for 5 minutes)

The reaction tubes are shaken and placed in a water bath (37° C.) for 20minutes, at which time the reaction is stopped by placing the tubes in aboiling water bath for 4 minutes. Washing buffer (0.5 mL, 0.1 M4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES)/0.1 M NaCl,pH 8.5) is added to each tube on an ice bath. The contents of each tubeare applied to an Aft-Gel 601 column (Biorad Laboratories, P.O. Box1229, 85A Marcus Drive, Melville, New York 11747) (boronate affinitygel, 1 mL bed volume) previously equilibrated with washing buffer. ³H!cAMP is washed with 2×6 mL washing buffer, and ³ H!5'AMP is theneluted with 4 mL of 0.25 M acetic acid. After vortexing, 1 mL of theelution is added to 3 mL of scintillation fluid in a suitable vial,vortexed and counted for ³ H!.

Inhibition is determined by the formula: ##EQU1## IC₅₀ is defined asthat concentration of compound which inhibits 50% of specific hydrolysisof ³ H!cAMP to ³ H!5'AMP.

For administration to humans to inhibit PDE_(IV) and in the treatment ofinflammatory conditions, AIDS, asthma, arthritis, bronchitis, chronicobstructive pulmonary disease, psoriasis, allergic rhinitis ordermatitis, oral dosages of the compounds of formula (I) or thepharmaceutically acceptable salts thereof, are generally in the range offrom 0.1-500 mg daily for an average adult patient (70 kg). Thus for atypical adult patient, individual tablets or capsules contain from 0.1to 50 mg of active compound, in a suitable pharmaceutically acceptablevehicle or carrier. Multiple tablets or capsules may be required to meetthe dosage requirements. Dosages for intravenous administration aretypically within the range of 0.1 to 10 mg per single dose as required.For intranasal or inhaler administration, the dosage is generallyformulated as a 0.1 to 1% (w/v) solution. In practice the physician willdetermine the actual dosage which will be most suitable for anindividual patient and it will vary with the age, weight and response ofthe particular patient. The above dosages are exemplary of the averagecase but there can, of course, be individual instances where higher orlower dosage ranges are merited, and all such dosages are within thescope of this invention.

For human use, the compounds of the formula (I) and the pharmaceuticallyacceptable salts thereof can be administered alone, but will generallybe administered in an admixture with a pharmaceutical diluent or carrierselected with regard to the intended route of administration andstandard pharmaceutical practice. For example, they may be administeredorally in the form of tablets containing such excipients as starch orlactose, or in capsules or ovales either alone or in admixture withexcipients, or in the form of elixirs or suspensions containingflavoring or coloring agents. They may be injected parenterally; forexample, intravenously, intramuscularly or subcutaneously. Forparenteral administration, they are best used in the form of a sterileaqueous solution which may contain other substances; for example, enoughsalts or glucose to make the solution isotonic. For topicaladministration, they are best used in the form of solutions, lotions,ointments, salves and the like.

Thus in a further aspect the invention provides pharmaceuticalcompositions comprising a compound of the formula (I), or apharmaceutically acceptable salts thereof, together with apharmaceutically acceptable diluent or carrier which are useful; ininhibiting PDE_(IV) ; in the treatment of inflammatory conditions and inthe treatment of AIDS, asthma, arthritis, bronchitis, chronicobstructive pulmonary disease, psoriasis, allergic rhinitis anddermatitis in mammals, especially humans.

This invention also provides methods of inhibiting PDE_(IV) in a mammalin need thereof which methods comprise administering to said mammal aPDE_(IV) inhibiting amount of a compound of the formula (I) or apharmaceutically acceptable salt thereof.

This invention further provides a method of treating an inflammatorycondition in a mammal in need thereof which comprises administering tosaid mammal an antiinflammatory amount of a compound of the formula (I)or a pharmaceutically acceptable salt thereof.

Further still, this invention provides a method of treating AIDS,asthma, arthritis, bronchitis, chronic obstructive pulmonary disease,psoriasis, allergic rhinitis, dermatitis or shock in a mammal in needthereof which comprises administering to said mammal an effective amountof a compound or a pharmaceutically acceptable salt thereof.

The present invention is illustrated by the following examples, but itis not limited to the details thereof.

EXAMPLE 13-(3-Cyclopentyloxy-4-methoxy)phenyl-2-isoxazoline-5-hydroxamic Acid

To a solution of sodium methoxide, prepared from 97 mg (4.2 mmol) ofsodium and 10 mL of methanol, was added 146 mg (2.1 mmol) ofhydroxylamine hydrochloride in a solution of 3 mL of methanol followedby 500 mg (1.5 mmol) of the compound of Preparation 10. After stirringfor about 16 h at RT, the solvent was evaporated and the residue wasdissolved in 50 mL of water and washed with ether (2×50 mL). The aqueouslayer was acidified to pH 1 with aqueous HCl solution and theprecipitate (231 mg) was filtered and recrystallized twice from CH₂ /Cl₂/EtOAc to give 52 mg of the title compound, mp 167°-168° C. ¹ H NMR(DMSO-D₆): 6 1.54-1.92 (8H, m), 3.48-3.67 (2 Hm), 3.78 (3 H, s),4.79-4.85 (1 H, m), 4.95 (1 H, t, J=8), 6.99 (1 H, d, J=9), 7.17 (1 H,d, J=9), 7.23 (1 H, s), 9.03 (1 H, s); Anal. Calc'd. for C₁₆ H₂₀ N₂ O₅:C, 59.99 ; H, 6.29; N, 8.74. Found: C, 59.82 H, 6.05; N, 8.65.

EXAMPLES 2-16

The following compounds having the formula shown below were preparedsubstantially according to the procedure of Example 1 substituting theindicated ester for that of the ester of Preparation 10. In the case ofExample 5, N-methyl-hydroxylamine hydrochloride was substituted forhydroxylamine hydrochloride.

    __________________________________________________________________________     ##STR7##                                                                     Ex Y.sup.1  Y.sup.2  R.sup.4                                                                         R.sup.5                                                                         Ester                                                                              M.P. (°C.)                                                                  Data                                       __________________________________________________________________________    2  OMe      O(CH.sub.2).sub.5 Ph                                                                   H H Cmpd. of                                                                           130-132                                                                            Anal. Calc'd for                                                    Prep 8    C.sub.22 H.sub.26 N.sub.2 O.sub.5 :                                           C,                                                                            66.32; H, 6.58; N,                                                            7.03. Found: C,                                                               66.23; H, 6.50; N,                                                            6.94                                       3  OMe      O(CH.sub.2).sub.5 Ph                                                                   Et                                                                              H Cmpd. of                                                                           169-171                                                                            Anal. Calc'd for                                                    Prep. 9   C.sub.24 H.sub.30 N.sub.2 O.sub.5.1/4H.                                       sub.2                                                                         O: C, 66.82; H,                                                               7.07; N, 6.49.                                                                Found: C, 67.13; H,                                                           7.03; N, 6.15                              4  OMe                                                                                     ##STR8##                                                                              Me                                                                              H Cmpd. of Prep. 12                                                                  171-173                                                                            Anal. Calc'd for C.sub.17 H.sub.22                                            N.sub.2 O.sub.5.1/2H.sub.2 O C, 59.41;                                        H, 6.70; N, 8.15. Found: C, 59.78; H,                                         6.38; N, 8.27                              5  OMe                                                                                     ##STR9##                                                                              H Me                                                                              Cmpd. of Prep. 11                                                                  146-148                                                                            Anal. Calc'd for C.sub.17 H.sub.22                                            N.sub.2 O.sub.5 : C, 61.07; H, 6.63;                                          N, 8.38. Found: C, 60.87; H, 6.52; N,                                         8.45                                       6  OMe      OMe      H H Cmpd. of                                                                           180-182                                                                            Anal. Calc'd for                                                    Prep. 22  C.sub.12 H.sub.14 N.sub.2 O.sub.5 :                                           C,                                                                            54.13; H, 5.30; N,                                                            10.52. Found: C,                                                              54.03; H, 5.12; N,                                                            10.60                                      7  OMe      OCH.sub.2 Ph                                                                           H H Cmpd. of                                                                           166-168                                                                            Anal. Calc'd for                                                    Prep. 23  C.sub.18 H.sub.18 N.sub.2 O.sub.5 :                                           C,                                                                            63.15; H, 5.30; H,                                                            8.18. Found: C,                                                               63.32; H, 5.37; H,                                                            8.09                                           ##STR10##                                                                             H        H H Cmpd. of Prep. 24                                                                  --   .sup.1 NMR (DMSO- d.sub.6): δ                                           3.48-3.68 (2H, m), 4.95 (1H, t, J=8),                                         5.43 (2H, s), 7.15 (2H, d, J=9),                                              7.59-7.69 (4H, m), 7.80 (1H, t, J=8),                                         8.01 (2H, t, J=7), 8.42 (1H, d, J=9),                                         9.04 (1H, s), 10.99 (1H, s). MS (m/e):                                        63 (M.sup.+)                               9  OCH.sub.2 Ph                                                                           H        H H Cmpd. of                                                                           190-192                                                                            .sup.1 H NMR (DMSO-                                                 Prep. 25  d.sub.6 : δ d 3.44-3.63                                                 (2H, m), 4.94 (1H, t,                                                         J=8), 5.15 (2H, s),                                                           7.08 (2H, d, J=8),                                                            7.32-7.46 (5H, m),                                                            7.62 (2H, d, J=8),                                                            9.03(1H, s); MS                                                               (m/e): 313 (M.sup.+ +1)                    10 H                                                                                       ##STR11##                                                                             H H Cmpd.of Prep. 13                                                                   151-153                                                                            Anal. Calc'd for C.sub.15 H.sub.18                                            N.sub.2 O.sub.4 : C, 9.65. Found: C,                                          62.00; H, 6;15; N, 9.36                    11                                                                                ##STR12##                                                                             OMe      H H Cmpd. of Prep. 14                                                                  136-138                                                                            Anal. Calc'd for C.sub.16 H.sub.20                                            N.sub.2 O.sub.5 : C, 59.99; H, 6.29;                                          N, 8.74. Found: C, 59.66; H, 6.21; N,                                         8.69                                       12 H        H        H H Cmpd. of                                                                           166-168                                                                            Anal. Calc'd for                                                    Prep. 17  C.sub.10 H.sub.10 N.sub.2 O.sub.3 :                                           C,                                                                            58.25; H, 4.89; N,                                                            13.59. Found: C,                                                              58.24; H, 4.49; N,                                                            13.45                                      13 OMe                                                                                     ##STR13##                                                                             Pr                                                                              H Cmpd. of Prep. 18                                                                  154-157                                                                            Anal. Calc'd for C.sub.19 H.sub.26                                            N.sub.2 O.sub.5 : C, 62.97; H, 7.23;                                          N, 7.73. Found: C, 62.61; H, 7.19; N,                                         7.54.                                      14 OMe                                                                                     ##STR14##                                                                             Bu                                                                              H                                                                                ##STR15##                                                                         135-138                                                                             ##STR16##                                 15 OMe                                                                                     ##STR17##                                                                             Ph                                                                              H                                                                                ##STR18##                                                                         180-182                                                                             ##STR19##                                 16                                                                                ##STR20##                                                                                        ##STR21##                                                                         111-133                                                                             ##STR22##                                    __________________________________________________________________________

    __________________________________________________________________________     ##STR23##                                                                         Ester                                                                         Cmpd. of Prep.                                                           Example                                                                            #      R.sup.3                                                                         R.sup.4                                                                         m MP (°C.)                                                                     α!.sub.D .sup.25                                                           Anal.                                              __________________________________________________________________________    17   28     H H 0 137-140°                                                                    +77°                                                                       Calc'd. for C.sub.16 H.sub.20 N.sub.2 O.sub.5                                 : C, 59.99; H,                                                            MeOH                                                                              6.29; N, 8.74. Found: C, 59.98; H,                                            6.62; N, 8.80.                                     18   29     H H 0 138-140°                                                                    -82°                                                                       Calc'd. for C.sub.16 H.sub.20 N.sub.2 O.sub.5                                 : C, 59.99; H,                                                            MeOH                                                                              6.29; N, 8.74.                                                                Found: C, 59.66: H, 6.44; N, 8.61.                 19   33     H H 1 139-141°                                                                    racemic                                                                           Calc'd. for C.sub.17 H.sub.22 N.sub.2 O.sub.5.1                               /4H.sub.2 O; C,                                                               60.02; H, 6.64; N, 8.26. Found: C,                                            59.63; H, 6.48; N, 8.15.                           20.sup.a                                                                           31     Me                                                                              H 0 184-186°                                                                    racemic                                                                           Calc'd. for C.sub.17 H.sub.22 N.sub.2 O.sub.5                                 : C, 61.01; H,                                                                6.58; N, 8.38.                                                                Found: C, 61.08; H, 6.88; N, 8.04.                 21   39     H Me                                                                              0 167-168°                                                                    +9°.sup.b                                                                  Calc'd. for C.sub.17 H.sub.22 N.sub.2 O.sub.5.1                               /4H.sub.2 O: C,                                                           CHCl.sub.3                                                                        60.25; H, 6.69; N, 8.27.                                                      Found: C, 60.43; H, 6.70; N, 8.23.                 22   40     H Me                                                                              0 153-155°                                                                    -14°.sup.b                                                                 Calc'd. for C.sub.17 H.sub.22 N.sub.2 O.sub.5.1                               /2H.sub.2 O: C,                                                           CHCl.sub.3                                                                        59.41; H, 6.70; N, 8.15.                                                      Found: C, 59.64; H, 6.65; N,                       __________________________________________________________________________                               8.03.                                               .sup.a trans isomer                                                           .sup.b These compounds are the resolved enantiomers of Example 4. The         enantiomeric purity was 99% as determined by chiral HPLC using a Chrom        Tech chiral column. Mobiie phase: 98:2 10 mM ammonium acetate buffer, pH      4.1: 2propanol; flow rate: 1 mL/min; detection: 230 nM; temperature:          ambient; injection volume: 20 μL                                      

PREPARATION 1 4-Methoxy-3(5-phenylpentyloxy)benzaldehyde Oxide

A mixture of 25.0 g (0.164 mol) of isovanillin, 26.9 g (0.164 mol) of5-phenyl-1-pentanol, 64.5 g (0.246 mol) of triphenylphosphine and 250 mLof THF was treated dropwise with 42.8 g (0.246 mol) of diethylazodicarboxylate. The mixture was heated to about 90° C. for about 6 hrsand then stirred overnight at RT. The solvent was evaporated and theresidue was diluted with 500 mL of EtOAc, washed with water (1×400 mL),1 N NaOH solution (2×400 mL), brine (1×400 mL), dried (MgSO₄), andevaporated to 119 g of a brown oil. Purification by flash chromatography(750 g of silica gel) using an EtOAc-hexane (3:7) eluant afforded 29.8 g(61%) of an oil. ¹ H NMR (CDCl₃): δ 1.42-1.92 (6 H, m), 2.61 (2 H, t,J=7), 3.91 (3 H, s), 4.03 (2 H, t, J=7), 6.91 (1 H, d, J=8), 7.10-7.40(m, 7 H), 9.77 (s, 1 H).

To a solution of 29.8 g (0.100 mol) of the above aldehyde in 300 mL of95% ethanol was added 13.7 g (0.197 mol) of hydroxylamine hydrochloridein 100 mL of water followed by 16.6 g (0.197 mol) of sodium bicarbonatein small portions (gas evolution|). The mixture was stirred for about 4h at RT and the ethanol was removed by evaporation. The residue wasdiluted with 250 mL of water and extracted with EtOAc (2×200 mL). Thecombined extracts were dried (MgSO₄) and evaporated to a yellow oilwhich was crystallized from hexane/ether to afford 15.0 g of the titlecompound, mp 65°-67° C. ¹ H NMR (CDCl₃): δ 1.46-1.93 (6 H, m), 2.62 (2H, t, J=7), 3.88 (3 H, s), 4.02 (2 H), J=7), 6.99-7.62 (m, 6 H), 7.49 (1H, s), 8.04 (1 H, s).

An additional 2.00 g of product was obtained as a second crop from thefiltrate, mp 67°-69° C. Evaporation of the filtrate and purification ofthe residue by flash chromatography using an EtOAc-hexane (2:3) eluantalso provided an additional 4.18 g of product, mp 64°-66° C.

PREPARATIONS 2-4

The following compounds having the formula shown below were prepared,substantially according to the procedure of Preparation 1, substitutingthe indicated phenol for isovanillin and the indicated alcohol for5-phenyl-1-pentanol. Compounds that were oils were purified by flashchromatography.

    __________________________________________________________________________     ##STR24##                                                                    Prep                                                                          #  Y.sup.1  Y.sup.2  Phenol                                                                             Alcohol                                                                              M.P. (°C.)                                                                  .sup.1 H NMR (CDCl.sub.3)               __________________________________________________________________________                                          δ:                                2  OMe                                                                                     ##STR25##                                                                             isovanillin                                                                        cyclopentanol                                                                        oil                                                                                 ##STR26##                              3  H                                                                                       ##STR27##                                                                              ##STR28##                                                                         cyclopentanol                                                                        oil                                                                                 ##STR29##                                  ##STR30##                                                                             OMe      vanillin                                                                           cyclopentanol                                                                        110-111                                                                             ##STR31##                              __________________________________________________________________________

PREPARATIONS 5-6

The following compounds having the formula shown below were prepared bycondensation of the indicated aldehyde with hydroxylamine hydrochloride,substantially according to the procedure of Preparation 1.

    __________________________________________________________________________     ##STR32##                                                                    Prep                                                                          #  Y.sup.1                                                                           Y.sup.2                                                                           Aldehyde                                                                             M.P. (°C.)                                                                  .sup.1 H NMR (DMSO-d.sub.6) δ:                   __________________________________________________________________________    5  OMe --OH                                                                              isovanillin                                                                          146-148                                                                            3.77 (3H, s), 6.92 (2H, s), 7.08 (1H,                                         s), 7.96 (1H, s), 9.16 (1H, s), 10.90                                         (1H, s)                                                6  OH  H   p-hydroxy-                                                                           115-118                                                                            6.77 (2H, d, J=9), 7.40 (2H, d,                                   benzaldehyde                                                                              J=9), 8.00 (1H1 s), 9.74 (1H, s),                                             10.83 (1H, s)                                          __________________________________________________________________________

PREPARATION 7 Ethyl 2-Methylenebutyrate

A mixture of 5.0 g (0.019 mol) of triethyl 2-phosphonobutyrate, 5.5 g(0.039 mol) of K₂ CO₃, 6.2 g (0.076 mol) of 37% aqueous formaldehydesolution, and 15 mL of water was heated to about 80° C. for about 45min. After cooling to RT, 75 mL of ether was added and the organic layerwas separated, washed with brine (1×20 mL), dried (MgSO₄), and filtered.The ether was carefully removed by distillation, leaving behind 2.1 g(87%) of the title compound as a clear oil which was used directlywithout further purification. ¹ H NMR (CDCl₃): δ 1.01 (3 H, t, J=7),1.24 (3 H, t, J=7), 2.26 (2 H, q, J=7), 4.14 (2 H, q, J=7), 5.45 (1 H,s), 6.06 (1 H, s).

PREPARATION 8 3-4-Methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazoline-5-carboxylic AcidEthyl Ester

To a mixture of 1.28 g (9.57 mmol) of N-chlorosuccinimide, 200 μl ofpyridine, and 200 mL of CH₂ Cl₂ was added 2.00 g (6.38 mmol) of thecompound of Preparation 1 in a solution of 15 mL of CH₂ Cl₂. An exothermwas observed after about 10 min and following about 2 h of stirring atRT, 644 mg (698 μl, 6.38 mmol) of ethyl acrylate was added followed by966 mg (1.33 ml, 9.57 mmol) of triethylamine. After the exothermsubsided, the mixture was stirred for about 2 h at RT. The mixture wasdiluted with 250 mL of CH₂ Cl₂ and washed with aqueous 1 N HCl solution,sat'd. aqueous NaHCO₃ solution, dried (Na₂ SO₄), and evaporated to anoil. Purification by flash chromatography (100 g of a silica gel) usingan EtOAc-hexane (2:3) eluant afforded 1.82 g (69%) of the title compoundas an oil. ¹ H NMR (CDCl₃): δ 1.29 (3 H, t, J=7), 1.40-1.91 (6 H, m),2.60 (2 H, t, J=7), 3.55-3.58 (2 H, m), 3.95 (3 H, s), 3.99 (2 H, t,J=7), 4.22 (2 H, q, J=7), 5.05-5.12 (1 H, m), 6.79 (1 H, d, J=8),6.95-7.31 (7 H, m).

    __________________________________________________________________________     ##STR33##                                                                    Prep                                M.P.                                      #   Y.sup.1  Y.sup.2  R.sup.4                                                                         X Oxime Olefin                                                                            (°C.)                                                                       .sup.1 H NMR (CDCl.sub.3)                                                     δ or Elemental                 __________________________________________________________________________                                             Analysis:                            9   OMe      O(CH.sub.2).sub.5 -Ph                                                                  Et                                                                              Et                                                                              Compound                                                                            Com-                                                                              oil  0.98 (3H, t, J=7), 1.30 (3H, t,                                               J=7), 1.48-2.03                                                of    pound    (8H, m), 2.62 (2H, t, J=7), 3.18                                              (1H, d, J=17),                                                 Preparation 1                                                                       of       3.76 (1H, d, J=17), 3.86 (3H,                                                 s), 4.01 (2H, q,                                                     Prepar-  J=7), 6.82 (1H, d, J=8), 7.01                                                 (1H, dd, J=2, 8),                                                    ation 7  7.15-7.33 (6H, m)                    10  OMe                                                                                     ##STR34##                                                                             H Et                                                                               ##STR35##                                                                           ##STR36##                                                                        oil                                                                                 ##STR37##                           11  OMe                                                                                     ##STR38##                                                                             H Me                                                                               ##STR39##                                                                           ##STR40##                                                                        101-102                                                                             ##STR41##                           12  OMe                                                                                     ##STR42##                                                                             Me                                                                              Et                                                                               ##STR43##                                                                           ##STR44##                                                                        77-79                                                                               ##STR45##                           13  H                                                                                       ##STR46##                                                                             H Me                                                                               ##STR47##                                                                           ##STR48##                                                                        oil                                                                                 ##STR49##                           14                                                                                 ##STR50##                                                                             OMe      H Me                                                                               ##STR51##                                                                           ##STR52##                                                                        oil                                                                                 ##STR53##                           15  OMe      OH       H Me                                                                              Compound                                                                            Methyl                                                                            75-95                                                                              3.56-3.60 (2H, m), 3.79 (3H, s),                                              3.90 (3H, s),                                                  of    acrylate 5.12 (1H, t, J=10), 5.66 (1H,                                                 s), 6.83 (1H, d,                                               Preparation 5  J=9), 7.13 (1H, dd, J=2, 9),                                                  7.24 (1H, d, J=2)*                   16  OH       H        H Me                                                                              Compound                                                                            Methyl                                                                            149-153                                                                            3.61-3.65 (2H, m), 3.83 (3H, s),                                              5.17 (1H, t,                                                   of    acrylate J=9), 5.80 (1H, bd s), 6.88 (2H,                                              d, J=9), 7.56                                                  Preparation 6  (2H, d, J=9)                         17  H        H        H Et                                                                              Benzalde-                                                                           Ethyl                                                                             40-41                                                                              1.50 (3H, t, J=7), 3.60-3.65                                                  (2H, m), 4.26 (2H,                                             hyde  acrylate q, J=7), 5.15 (1H, t, J=9),                                                   7.37-7.42 (3H, m),                                             oxime          7.64-7.70 (2H, m)                    18  OMe                                                                                     ##STR54##                                                                             Pr                                                                              Et                                                                              Compound of Preparation 2                                                           Com- pound of Prep. 34                                                            oil  0.94 (3H, t, J=8), 1.30 (3H, t,                                               J=8), 1.32-1.99 (12H, m), 3.20                                                (1H, d, J=17), 3.76 (1H, d,                                                   J=17), 3.85 (3H, s), 4.18-4.32                                                (2H, m), 4.72- 4.82 (1H, m),                                                  6.82 (1H, d, J=8), 7.00 (1H, dd,                                              =2 and 8), 7.34 (1H, d, J=2)         19  OMe                                                                                     ##STR55##                                                                             Bu                                                                              Et                                                                              Compound of Preparation 2                                                           Com- pound of Prep. 35                                                            53-36                                                                              0.90 (3H, t, J=8), 1.30 (3H, t,                                               J=8), 1.22-1.98 (14H, m), 3.20                                                (1H, d, J=17), 3.78 (1H, d,                                                   J=17), 3.86 (3H, s), 4.20-4.29                                                (2H, m), 4.75- 4.85 (1H, m),                                                  6.82 (1H, d, J=8), 7.01 (1H, dd,                                              =2 and 8), 7.34 (1H, d, J=2)         20  OMe                                                                                     ##STR56##                                                                             Ph                                                                              Et                                                                              Compound of Preparation 2                                                           Com- pound of Prep. 36                                                            98-100                                                                             Anal. Calc'd for: C.sub.24                                                    H.sub.27 NO.sub.5 : C, 70.39; H,                                              6.65; N, 3.42. Found: C, 70.30,                                               H, 6.81; N, 3.56                     21                                                                                 ##STR57##            Compound of Preparation 2                                                           Methyl 1-cyclo- pente- noate                                                      oil  1.60-2.37 (14H, m), 3.79 (3H,                                                 s), 3.86 (3H, s), 4.21 (1H, dd,                                               J=3 and 7), 4.75-4.80 (1H, m),                                                6.82 (1H, d, J=9), 7.05 (1H, dd,                                              J=2 and 9), 7.34 (1H,                __________________________________________________________________________                                             J=2)                                  *The NMR shows a contaminant which is most likely a product resulting fro     chlorination of the aromatic ring.                                       

PREPARATION 22 3-(3,4-Dimethoxyphenyl)-2-isoxazoline-5-carboxylic AcidMethyl Ester

To a solution of 1.5 g (6.00 mmol) of the compound of Preparation 15 in25 mL of DMF was added 91 0 mg of K₂ CO₃ (6.60 mmol) and 0.41 mL (940mg, 6.6 mmol) of methyl iodide. The mixture was heated to about 50° C.and the progress of the reaction was monitored by TLC. Additional 0.4 mLportions of methyl iodide were added at about 1 and 2 h, respectively.After about 2 h of additional heating, the reaction was cooled, dilutedwith 250 mL of water, extracted with EtOAc (3×100 mL), dried (MgSO₄),and evaporated to an oil. Purification by flash chromatography using anEtOAc-hexane (1:3) eluant afforded 270 mg of the title compound, mp106°-108° C. ¹ H NMR (CDCl₃): δ 3.59-3.63 (2 H, m), 3.79 (3 H, s), 3.89(3 H, s), 5.15 (1 H, t, J=8), 6.83 (1 H, d, J=8), 7.03 (1 H, dd, J=2,8), 7.37 (1 H, d, J=8); MS (m/e): 266 (M⁺ +1).

PREPARATIONS 23-25

The following compounds having the formula shown below were prepared,substantially according to the procedure of Preparation 22, substitutingthe indicated phenol for that of Preparation 15 and the indicatedalkylating agent for methyl iodide.

    __________________________________________________________________________     ##STR58##                                                                    Prep             Alkylating                                                   #  Y.sup.1                                                                             Y.sup.2                                                                          Phenol                                                                             Agent M.P. (°C.)                                                                  Data                                              __________________________________________________________________________    23 OMe   OBn                                                                              Cmpd of                                                                            PhCH.sub.2 Br                                                                       183-185                                                                            .sup.1 H NMR (CDCl.sub.3): δ 3.54-                      Prep 15         3.58 (2H, m), 3.79 (3H, s),                                                   3, 89 (3H, s), 5.10-5.26                                                      (1H, m), 5.13 (2H, s), 6.86                                                   (1H, d, J=9), 7.06 (1H, dd,                                                   J=2, 8), 7.32-7.40 (6H, m);                                                   MS 9m/e): 342 (M.sup.+ + 1)                       24                                                                                ##STR59##                                                                          H                                                                                 ##STR60##                                                                          ##STR61##                                                                          112-113                                                                             ##STR62##                                        25 OCH.sub.2 Ph                                                                        H  Cmpd of                                                                            PhCH.sub.2 Br                                                                       127-128                                                                            Anal. Calc'd for                                              Prep 16         C.sub.18 H.sub.17 NO.sub.4 : C, 69.43; H,                                     5.50; N, 4.50. Found: C,                                                      69.18; H, 5.31; N, 4.59                           __________________________________________________________________________

PREPARATION 263aR-(3aα,6α,7αβ!-Hexahydro-8,8-dimethyl-1-(1-oxo-2-propenyl)-3H-3a,6-methano-2,1-benzisothiazole2,2-Dioxide

The title compound was prepared according to the method of Curran andHeffner (Curran, D. P., Heffner, T. A., J. Org. Chem., 1990, 55, 4585)starting with (+)-L-2,10-camphor suitam, which was purchased from Fluka.

Into a 1 L 3-neck round bottom flask fitted with reflux condenser, N₂inlet, rubber septum and glass stopper was placed 4.03 g (0.084 mol) of50% NaH dispersion, 400 mL of toluene, and 12.0 g (0.056 mol) of(+)-10,2-camphor suitam. After stirring for 1 h. at RT, 594 mg (0.006mol) of CuCl followed by 9.10 mL (0.056 mol) of acryloyl chloride wereadded and stirring was continued overnight at RT. The mixture was thentreated with 15 mL of water, evaporated, diluted with water (200 mL),and extracted with EtOAc (3×200 mL). The combined extracts were dried(MgSO₄) and evaporated to a solid. Purification by flash chromatography(1 kg of silica gel) using a 3:7 EtOAc-hexane eluant afforded a whitesolid which was triturated with ether to provide 7.4 g of the titlecompound, mp 179°-182° C.

PREPARATION 273aS-(3aα,6α,7αβ!-Hexahydro-8,8-dimethyl-1-(1-oxo-2-propenyl)-3H)-3a,6-methano-2,1-benzisothiazole2,2-Dioxide

The title compound was prepared according to the procedure ofPreparation 26, however, starting with (-)-D-2,10-camphor suitam, whichwas purchased from Fluka.

    __________________________________________________________________________     ##STR63##                                                                                                        α!.sub.D .sup.25                    Prep.                                                                            R.sup.3                                                                         R.sup.4                                                                         Q            Olefin    MP (°C.)                                                                    CHCl.sub.3                                                                        Data                                   __________________________________________________________________________    28.sup.a                                                                         H H                                                                                ##STR64##                                                                                  ##STR65##                                                                              form +187°                                                                       ##STR66##                             29.sup.a                                                                         H H                                                                                ##STR67##                                                                                  ##STR68##                                                                              foam +46°                                                                        ##STR69##                             30 H H (CH.sub.2).sub.2 OH                                                                        CH.sub.2 CH(CH.sub.2).sub.2 OH                                                          89-91                                                                              racemic                                                                           Anal. Calc'd. for C.sub.17                                                    H.sub.23 NO.sub.4 : C, 66.86;                                                 H, 7.59; N, 4.59. Found: C, 66.71;                                            H,                                                                            7.77; N, 4.64.                         31.sup.b                                                                         H Me                                                                              CO.sub.2 Me  ethyl     oil  racemic                                                                           .sup.1 H-NMR(CDCl.sub.3):                                                     1.40-2.05 (8H, m), 1.43                                    crotonate          (3H, d, J=7), 3.69 (3H, s), 3.84                                              (3H, s),                                                                      4.01 (1H, d, J=7), 4.74-4.82 (1H,                                             m),                                                                           4.95-5.06 (1H, m), 6.79 (1H, d,                                               J=8),                                                                         7.05 (1H, dd, J=2, 8), 7.31 (1H,                                              d,                                                                            J=2).                                  __________________________________________________________________________     .sup.a less polar diastereomer (R.sub.f 0.61; 1:1 ethertoluene); .sup.b       trans stereochemistry                                                    

PREPARATION 323-(3-Cyclopentyloxy-4-methoxy)phenyl-2-isoxazoline-5-acetic Acid

To a solution of 1.85 g (6.06 mmol) of the compound of Preparation 30 in50 mL of acetone chilled to about 0° C. in an ice bath was addeddropwise 9.70 mL (12.1 mmol) of a 1.25 M solution of Jones reagent. Theice bath was allowed to melt, and after about 4 h. of stirring anadditional 2.00 mL of Jones reagent was added and stirring was continuedovernight. Excess reagent was quenched by the addition of 10 mL ofisopropanol, and the solids were removed by filtration. The filtrate wasconcentrated and the residue was taken up in 150 mL of EtOAc, washedwith water (2×100 mL), dried (MgSO₄), and evaporated to a yellow oil.Crystallization from ether-hexane gave 1.06 g of the title compound, mp123°-126° C.

¹ H-NMR (CDCl₃): δ 1.55-2.06 (8 H, m), 2.66-3.59 (4 H, m), 3.87 (3 H,x), 4.78-4.87 (1 H, m), 5.02-5.15 (1 H, m), 6.84 (1 H, d, J=8), 7.02 (1H, dd, J=1, 8), 7.37 (1 H, d, J=2).

PREPARATION 333-(3-Cyclopentyloxy-4-methoxy)phenyl-2-isoxazoline-5-acetic Acid MethylEster

A solution of 530 mg of the compound of Preparation 32 in 5 mL of MeOHwas saturated with HCl gas and the mixture was stirred for about 3 h. atRT protected from atmospheric moisture with a CaCl₂ tube. The mixturewas concentrated and the residue was taken up in 50 mL of EtOAc, washedwith saturated aqueous NaHCO₃ solution (2×50 mL), dried (MgSO₄), andevaporated to 530 mg of an oil. Purification by flash chromatography (25g of silica gel) using a 2:3--EtOAc:hexane eluant gave an oil which wascrystallized from hexane-ether to afford 323 mg of the title compound asa white solid, mp 78°-80° C.

Anal. Calc'd. for C₁₈ H₂₃ NO₅ ; C, 64.85; H, 6.95; N, 4.20. Found: C,64.49; H, 7.08; N, 4.13.

PREPARATIONS 34-36

The following compounds having the formula shown below were prepared asoils substantially according to the procedure of Preparation 7substituting the indicated ester for triethylphosphonobutyrate.

    ______________________________________                                         ##STR70##                                                                    Prep. #  R.sup.4                                                                              Ester          .sup.1 H-NMR(CDCl.sub.3):                      ______________________________________                                                                       δ                                        34       Pr     triethyl       0.90 (3H, t, J=7),                                             phosphonopentanoate                                                                          1.28 (3H, t, J=7),                                                            1.40-1.53 (2H, m),                                                            2.25 (2H, dt, J=1                                                             and 7), 4.17 (2H, q,                                                          J=7), 5.48 (1H, q,                                                            J=1), 6.11 (1H, t,                                                            J=11)                                          35       Bu     triethyl       0.90 (3H,t, J=7),                                              phosphonohexanoate                                                                           1.29 (3H, t, J=7),                                                            1.26-1.48 (4H, m),                                                            2.28 (2H, t, J=7),                                                            4.19 (2H, q, J=7),                                                            5.49 (1H, q, J=1),                                                            6.11 (1H, t, J=1)                              36       Ph     triethyl       1 .32 (3H, t, J=7),                                            phosphonophenylacetate                                                                       4.28 (2H, q, J=7),                                                            5.88 (1H, d, J=1),                                                            6.34 (1H, d, J=1),                                                            7.20-7.45 (5H, m)                              ______________________________________                                    

PREPARATIONS 37 and 38 Less Polar Diastereomer of N-(S)-α-Methylbenzyl!-3-(3-cyclopentyloxy-4-methoxy)phenyl-5-methyl-2-isoxazoline-5-carboxamide(Preparation 37) More Polar Diastereomer of N-(S)-α-Methylbenzyl!-3-(3-Cyclopentyloxy-4-methoxy)phenyl-5-methyl-2-isoxazoline-5-carboxamide(Preparation 38)

A solution of 5.00 g (14 mmol) of the compound of Preparation 12 in 100mL of absolute ethanol was treated with 2.36 g (42 retool) of KOH andthe mixture was stirred for about 4 hr at RT. An additional equivalentof KOH was added and stirring was continued for about 3 days. Themixture was concentrated, diluted with water, acidified with aqueous 1 NHCl solution, and extracted with EtOAc (2×100 mL). The combined extractswere dried (MgSO₄), evaporated, and triturated with hexane-ether to give3.46 g of 3-3-cyclopentyloxy-4-methoxy!phenyl-5-methyl-2-isoxazoline-5-carboxylicacid, mp 153°-154°.

A mixture of 3.00 g (94 mmol) of the above compound, 100 mL of benzene,and 2.46 mL (28.2 mmol) of oxalyl chloride was heated to reflux forabout 3 hr. The mixture was concentrated, diluted with 100 mL of CH₂Cl₂, and treated with 2.42 mL (18.8 mmol) of S-(-)-α-methylbenzylamine.After stirring for about 16 hr at RT, the mixture was concentrated,diluted with 200 mL of EtOAc, washed with aqueous 1 N HCl solution(2×100 mL), saturated aqueous NaHCO₃ solution (2×100 mL), dried (Na₂SO₄), and evaporated. The residual solid (5.76 g) was purified by flashchromatography over 600 g of silica gel using 15-20% ether-toluene aseluant. Following a 500 mL pre-fraction, 35 ml-fractions were collected.Fractions 59-68 were pooled and evaporated to give 630 mg of thecompound of Preparation 37, mp 154°-156° C.; R_(f) =0.20, 20%ether-toluene. Anal. calculated for C₂₅ H₃₀ N₂ O₄ : C, 71.06; H, 7.16;N, 6.63. Found: C, 71.13; H, 7.42; N, 6.76.

Fractions 82-104 were pooled and concentrated to 720 mg of a white solidwhich was triturated with hexane-ether to give 596 mg of a white solid,mp 165°-167° C. Recrystallization from ether-CH₂ Cl₂ afforded 435 mg ofthe compound of Preparation 38, mp 167°-168° C. An additional 1.03 g ofthe compound of Preparation 38, mp 166°-167° C., was obtained byrecrystallization (ether-CH₂ Cl₂) of the combined evaporated residues ofthe mother liquor and Fractions 69-81. Anal. calculated for C₂₅ H₃₀ N₂O₄ : C, 71.06; H, 7.16; N, 6.63. Found: C, 70.89; H, 7.40; N, 6.77.

PREPARATION 39(+)-3-(3-Cyclopentyloxy-4-methoxy)phenyl-5-methyl-2-isoxazoline-5-carboxylicAcid Methyl Ester

Into a flame-dried, 3-neck round-bottom flask under N₂ was placed asuspension of 549 mg (3.56 mmol) of 26% KH in mineral oil. After removalof the mineral oil by 2 successive hexane washes, the bare hydride wassuspended in 35 mL of THF and a solution of 750 mg (1.78 mmol) of thecompound of Preparation 37 in 35 mL of dry THF was added dropwise. Afterthe bubbling subsided, 161 μl (2.67 mmol) of carbon disulfide was added.The mixture was stirred for about 16 hr at RT and was quenched by theaddition of 6 mL of water. The THF was evaporated and the residue wasdiluted with saturated aqueous NaHCO₃ solution and washed with EtOAc(2×100 mL). The aqueous layer was acidified to pH 3 with aqueous 6 N HClsolution, extracted with EtOAc (2×100 mL), dried (MgSO₄), and evaporatedto 217 mg of an orange oil.

A solution of the above oil in 20 mL of MeOH was saturated with HCl gasand stirred for about 16 hr at RT. The mixture was concentrated, dilutedwith 50 mL of EtOAc, dried (MgSO₄), and evaporated to a yellow solid.Purification by flash chromatography over 12 g of silica gel using a 60%EtOAc-hexane eluant afforded 131 mg of the title compound aftertrituration in hexane-ether, mp 127°-128° C. α!_(C) ²⁵ +100° (c=0.64,CHCl₃). Anal. calculated for C₁₈ H₂₃ NO₅ •1/4H₂ O: C, 63.99; H, 7.01; N,4.15. Found C, 64.03; H, 6.96; N, 4.15.

PREPARATION 40(-)-3-(3-Cyclopentyloxy-4-methoxy)phenyl-5-methyl-2-isoxazoline-5-carboxamide

The title compound was prepared substantially according to Procedure 39substituting the compound of Preparation 38 for the compound ofPreparation 37; mp 124°-125° C.; α!_(C) ²⁵ -101° (c=0.61, CHCl₃). Anal.calculated for C₁₈ H₂₃ NO₅ •1/4H₂ O; C, 63.99; H, 7.01; N, 4.15. Found:C, 64.04; H, 7.00; N, 4.17.

What is claimed is:
 1. A compound of the formula ##STR71## the racemic,racemic-diastereomeric mixtures and optical isomers of said compoundsand the pharmaceutically acceptable salts thereof whereinm is 0, 1, 2 or3; n is 0, 1, 2 or 3; Y¹ and Y² are independently selected from thegroup consisting of hydrogen, (C₁ -C₆) alkyl, optionally substitutedphenylalkyl having 1 to 6 carbons in the alkyl portion, optionallysubstituted phenoxyalkyl having 1 to 6 carbons in the alkyl portion, (C₃-C₇)cycloalkyl, difluoromethyl, trifluoromethyl, fluoro, chloro, bromo,iodo, --OR¹ and --OR² ;wherein the aromatic portion of the optionallysubstituted phenylalkyl, and the aromatic portion of the optionallysubstituted phenoxyalkyl are optionally independently substituted with(C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, halogen or CF₃ ; R¹ is (C₁ -C₄)alkyl,phenylalkyl having one to four carbon atoms in the alkyl portion,fluoromethyl, difluoromethyl, trifluoromethyl, or --(CH₂)_(q) -quinolinewherein q is 1, 2 or 3; R² is (C₁ -C₃)alkyl, (C₃ -C₇)cycloalkyl,alkoxyalkyl having 3 to 7 carbons in the alkoxy portion and 2 and 4carbons in the alkyl portion, optionally substituted phenoxyalkyl having2 to 6 carbons in the alkyl portion, optionally substituted phenylalkylhaving 1 to 6 carbons in the alkyl portion, bicycloalkyl having 6 to 9carbons or optionally substituted indanyl;wherein the aromatic portionof the optionally substituted phenylalkyl, the aromatic portion of theoptionally substituted phenoxyalkyl and the optionally substitutedindanyl are optionally substituted with (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy,halogen or CF₃ ; R³ is hydrogen, (C₁ -C₃)alkyl, fluoro(C₁ -C₃)alkylhaving 1 to 3 fluoro atoms, mono-hydroxyalkyl having 1 to 3 carbons oralkoxyalkyl having 1 to 3 carbons in the alkyl portion and 1 to 3carbons in the alkoxy portion; R⁴ is hydrogen, (C₁ -C₅)alkyl, fluoro(C₁-C₅)alkyl having 1 to 3 fluoro atoms, mono-hydroxyalkyl having 1 to 3carbons, phenyl, alkoxyalkyl having 1 to 3 carbons in the alkyl portionand 1 to 3 carbons in the alkoxy portion, aminoalkyl having 1 to 3carbons, ##STR72## wherein X¹ is (C₁ -C₃)alkyl and n is an integer from1 to 3, N-alkylaminoalkyl having 1 to 3 carbons in the alkylaminoportion and 1 to 3 carbons in the alkyl portion, (C₃ -C₇)cycloalkyl orN,N-dialkylaminoalkyl having a total of 2 to 6 carbons in thedialkylamino portion and 1 to 3 carbons in the alkyl portion; R⁵ ishydrogen or (C₁ -C₃)alkyl; or R³ and R⁴ are taken together with thecarbon atoms to which they are attached and form a carbocyclic ringhaving 4 to 7 carbon atoms provided that when R³ is hydrogen, R⁴ ishydrogen, R⁵ is hydrogen, m is 1 and n is 0 then Y¹ and Y² are notfluoro, chloro, bromo, or iodo.
 2. A compound according to claim 1 or apharmaceutically acceptable salt thereof wherein Y¹ is --OR¹ and isattached to the 4-position of the phenyl ring and Y² is --OR² and isattached to the 3-position of the phenyl ring.
 3. A compound accordingto claim 2 or a pharmaceutically acceptable salt thereof wherein R¹ is(C₁ -C₄)alkyl, phenylalkyl having one to four carbon atoms in the alkylportion or --(CH₂)_(q) -quinoline; m is 0 and n is
 0. 4. A compoundaccording to claim 3 or a pharmaceutically acceptable salt thereofwherein R² is phenylalkyl having 1 to 6 carbons in the alkyl portion,(C₃ -C₇)cycloalkyl, or (C₁ -C₃)alkyl.
 5. A compound according to claim 4or a pharmaceutically acceptable salt thereof wherein R² is5-phenylpentyl, benzyl, cyclopentyl or methyl.
 6. A compound accordingto claim 5 or a pharmaceutically acceptable salt thereof wherein R³ ishydrogen.
 7. A compound according to claim 6 or a pharmaceuticallyacceptable salt thereof wherein R⁴ is hydrogen or (C₁ -C₅)alkyl.
 8. Acompound according to claim 7 or a pharmaceutically acceptable saltthereof wherein R⁵ is hydrogen or (C₁ -C₃)alkyl.
 9. A compound accordingto claim 8 or a pharmaceutically acceptable salt thereof wherein R¹ ismethyl; R² is cyclopentyl; R⁴ is hydrogen; and R⁵ is hydrogen.
 10. Thelevorotatory (negative rotation) enantiomer of the compound according toclaim 9 or a pharmaceutically acceptable salt thereof.
 11. A compoundaccording to claim 8 or a pharmaceutically acceptable salt thereofwherein R¹ is methyl; R² is cyclopentyl; R⁴ is methyl; and R⁵ ishydrogen.
 12. The levorotatory (negative rotation) enantiomer of thecompound according to claim 11 or a pharmaceutically acceptable saltthereof.
 13. A pharmaceutical composition comprising an effective amountof a compound according to claim 1 or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable diluent or carrier.
 14. Amethod of inhibiting phosphodiesterase type IV in a mammal in needthereof which comprises administering to said mammal a phosphodiesterasetype IV inhibiting amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof.
 15. A method of treating aninflammatory condition in a mammal which comprises administering to saidmammal an antiinflammatory amount of a compound according to claim 1 ora pharmaceutically acceptable salt thereof.
 16. A method of treatingasthma, arthritis, bronchitis, chronic obstructive pulmonary disease,psoriasis, allergic rhinitis, dermatitis or shock in a mammal whichcomprises administering to said mammal an effective amount of a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof.